# Establishing Mechanisms of LOX-1-Dependent Immune Regulation During Pneumonia

> **NIH NIH R00** · UNIVERSITY OF IOWA · 2024 · $249,000

## Abstract

Abstract
Pneumonia is the leading cause of infection-related deaths worldwide, a fact that is set to rise exponentially
with the SARS-CoV2 pandemic. Recovery from pneumonia requires both clearance of the pathogen and
resolution of infection, the latter of which is critical to resume normal lung function. While both processes are
important to host health, there is vastly less known about the mechanisms that regulate resistance to and
resolution of tissue injury during pneumonia, representing a large knowledge gap in our understanding of the
biology of the lung and its repair processes. Here, we propose that lectin-like oxidized low-density lipoprotein
receptor-1 (LOX-1) modulates acute pulmonary inflammation in way that promotes resolution through
reprogramming of leukocyte response. LOX-1 is a class E scavenger receptor, primarily known for its role in
promoting vascular inflammation during atherosclerosis. In direct contrast, our data suggests that LOX-1 has a
unique function in the lung, where it prevents edematous lung injury and inflammation, independent of bacterial
clearance in murine models of Escherichia coli and Streptococcus pneumoniae pneumonia. Moreover, LOX-1
and its major ligand oxidized low-density lipoprotein (oxLDL) are elevated in patients with ARDS as a result of
a confirmed diagnosis of pneumonia. Analysis of the cellular expression of LOX-1 in the lung revealed that
alveolar macrophages and recruited (airspace) neutrophils are uniquely enriched for LOX-1 expression.
Hematopoietic cells are also likely sources of LOX-1-dependent protection, as LOX-1-/- (WT recipient) chimeras
are significantly more protected from injury than WT (LOX-1-/- recipient) chimeras during pneumonia.
Assessment of the specific effects of LOX-1 inhibition on alveolar macrophages demonstrated that with
inhibition macrophages are skewed towards inflammation and exhibit metabolic changes associated with
increased glycolysis and lower fatty acid oxidation consistent with inflammatory macrophages. Moreover, we
discovered that recruited neutrophils differ in their expression of LOX-1, where about half of neutrophils are
positive during infection. Curiously, we also found phenotypic differences associated with LOX-1+ neutrophils
that suggest increased cholesterol metabolism, which may uniquely promote tissue resolution. Taken together,
leukocytes are an important source of LOX-1 and are likely responsible for LOX-1-dependent protection during
pneumonia. However, whether and how LOX-1 elicits its protective effects on leukocytes is not known. Thus,
we propose a central hypothesis that LOX-1 signaling evokes tissue-protective mechanisms in leukocytes
(K99), that are associated with metabolic changes consistent with reduced inflammation and increased tissue
recovery (R00). Results from our investigations will be the first to elucidate how LOX-1 is regulated at the
transcriptional and metabolic level in the unique microenvironment of the lung, where it likely faci...

## Key facts

- **NIH application ID:** 11103650
- **Project number:** 4R00HL159258-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Filiz Korkmaz
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2024-07-22 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11103650

## Citation

> US National Institutes of Health, RePORTER application 11103650, Establishing Mechanisms of LOX-1-Dependent Immune Regulation During Pneumonia (4R00HL159258-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11103650. Licensed CC0.

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